Share This Story!

UW team unravels mystery with DNA sequencing

Researchers from the University of Wisconsin-Madison have used DNA sequencing to unravel an 85-year-old mystery, pinpointing the genetic cause for Mauriac syndrome, a rare condition that affects children with poorly controlled Type 1 diabetes.

Researchers from the University of Wisconsin-Madison have used DNA sequencing to unravel an 85-year-old mystery, pinpointing the genetic cause for Mauriac syndrome, a rare condition that affects children with poorly controlled Type 1 diabetes.

The syndrome, first described 85 years ago by the French doctor Pierre Mauriac, is marked by massive enlargement of the liver, growth failure and delayed puberty. The afflicted children have Type 1 diabetes and are unable to control their blood sugar.

Until now, scientists and doctors were unable to say what caused the syndrome, which affects less than 1 percent of children with Type 1 diabetes.

The discovery of the cause, announced in the journal Diabetes, was made by a team led by Michael MacDonald, a UW professor emeritus who has been studying Type 1 diabetes for decades. He cautioned that although the discovery increases understanding of Mauriac syndrome, it is unlikely to lead to an improved treatment anytime soon.

Researchers at UW have been collecting DNA from several thousand patients with Type 1 diabetes. They conducted their latest study by examining the DNA of one patient, a young man with Mauriac syndrome. They also sequenced DNA from both of the man's parents.

The scientists sequenced eight genes involved in glycogen metabolism, the important process of breaking down chains of glucose molecules.

"It was a lot of work ," MacDonald explained. "We had to read all of these sequences, every nucleotide."

Nucleotides are the individual points on the genetic script, each one a chemical base, that collectively make up the human genome. There are 3.2 billion base pairs in the entire genome; MacDonald's team targeted just a portion of those.

The scientists found the crucial mutation that causes Mauriac syndrome in a gene called PHKG2. The gene encodes an enzyme that plays a crucial role in breaking down glycogen in the liver. The mutation results in an abnormal enzyme that disrupts the process of breaking down glycogen.

In patients with Type 1 diabetes this disruption combines with high blood sugar so that instead of breaking down, the glycogen in the liver accumulates. As a result, the liver becomes enlarged.

After identifying the mutation, MacDonald and his colleagues sequenced the DNA of 250 patients with Type 1 diabetes who did not have enlarged livers. None had the mutation possessed by the patient with the enlarged liver.

The UW scientists also found that although the patient's father did have Type 1 diabetes, he did not have the mutation and also did not have an enlarged liver.

Alvin C. Powers, director of the Vanderbilt Diabetes Center, was not involved in the study but called it "very, very nice work."

"Genetics," he added, "is playing an increasingly important role in understanding diabetes."